Interim analysis of the effects of exenatide treatment on A1C, weight and cardiovascular risk factors over 82 weeks in 314 overweight patients with type 2 diabetes.

AIM: Exenatide, an incretin mimetic for the adjunct treatment of type 2 diabetes (DM2), reduced A1C and weight in 30-week placebo-controlled trials. This analysis examined the effects of exenatide on glycaemic control and weight over an 82-week period in patients with DM2 unable to achieve adequate glycaemic control with sulphonylurea (SU) and/or metformin (MET). METHODS: This interim analysis is of 314 patients who received exenatide in the 30-week placebo-controlled trials and subsequently in 52 weeks of open-label uncontrolled extension studies for 82 weeks of exenatide in total. Patients continued their SU and/or MET regimens throughout. RESULTS: Patients completed 82 weeks of exenatide treatment [n = 314, 63% M, age 56 +/- 10 years, weight 99 +/- 21 kg, body mass index 34 +/- 6 kg/m2, A1C 8.3 +/- 1.0% (mean +/- SD)]. Reduction in A1C from baseline to week 30 [-0.9 +/- 0.1% (mean +/- SE)] was sustained to week 82 (-1.1 +/- 0.1%), with 48% of patients achieving A1C < or = 7% at week 82. At week 30, exenatide reduced body weight (a secondary endpoint) from baseline (-2.1 +/- 0.2 kg), with progressive reduction at week 82 (-4.4 +/- 0.3 kg). Similar results were observed for the intent-to-treat population (n = 551), with reductions in A1C and weight at week 82 of -0.8 +/- 0.1% and -3.5 +/- 0.2 kg respectively. The 82-week completer cohort showed statistically significant improvement in some cardiovascular risk factors. The most frequent adverse events were generally mild-to-moderate nausea and hypoglycaemia. CONCLUSION: In summary, 82 weeks of adjunctive exenatide treatment in patients with DM2 treated with SU and/or MET resulted in sustained reduction in A1C and progressive reduction in weight, as well as improvement in some cardiovascular risk factors.

Direct recruitment of N-myc to target gene promoters.

The N-myc gene is amplified in 20-25% of human neuroblastomas, and this amplification serves as a poor prognostic factor. However, few genes have been determined to be direct targets of N-myc. Our current studies focused on identifying N-myc target genes, especially those affected in cells such as neuroblastomas that have high levels of N-myc protein. To pursue this goal, we performed differential expression screens with cell-culture systems containing high versus low levels of N-myc. The design of our experiments was such that we should identify genes both upregulated and downregulated by N-myc. Accordingly, we identified 22 genes upregulated by N-myc and one gene downregulated by N-myc. However, only five of these genes responded to increased N-myc levels in more than one system. Further analysis of the regulation of these genes required determining whether they were direct or indirect targets of N-myc. Therefore, we used a formaldehyde crosslinking and immunoprecipitation procedure to determine whether N-myc was bound to the promoters of these putative target genes in living cells. We found that low levels of N-myc were bound to the promoters of the telomerase and prothymosin genes in neuroblastoma cells having low amounts of N-myc but that the amounts of N-myc bound to these promoters greatly increased with overexpression of N-myc. However, the amount of max bound to the promoters was high before and after induction of N-myc. Therefore, our studies suggest that N-myc competes with other max partners for binding to target promoters. Our use of the chromatin immunoprecipitation assay suggests a molecular explanation for the consequences of amplification of the N-myc gene in neuroblastomas.

CAD, a c-Myc target gene, is not deregulated in Burkitt's lymphoma cell lines.

Although the Myc family of transcription factors is upregulated in many human tumors, it is unclear which genes are targets for the deregulated Myc. Previous studies suggest that hamster and rat carbamoyl phosphate synthase, aspartate transcarbamylase, dihydroorotase Cad genes are regulated by c-Myc. In fact, of all putative target genes thought to be activated by c-Myc, only the Cad gene showed loss of growth regulation in rat cells nullizygous for c-Myc. However, it was unknown whether upregulation of CAD, which performs the first three rate-limiting steps of pyrimidine biosynthesis, contributes to c-Myc's role in human neoplasia. To explore this possibility, we cloned the human cad promoter. We found that c-Myc could bind to an E box in the human cad promoter in gel shift assays and that growth regulated transcription from the human cad promoter was dependent on this c-Myc binding site. However, the increased amount of c-Myc found in Burkitt's lymphoma cell lines did not lead to increased cad mRNA levels. Thus, we suggest that although c-Myc is clearly important for the normal transcriptional control of the cad promoter, it is unlikely that increased levels of CAD are important mediators of c-Myc-induced neoplasia. Therefore, an understanding of the mechanism by which overexpressed c-Myc contributes to the development of Burkitt's lymphoma requires the identification of additional c-Myc target genes.

Spatially restricted hypopigmentation associated with an Ednrbs-modifying locus on mouse chromosome 10.

We have used the varied expressivity of white spotting (hypopigmentation) observed in intrasubspecific crosses of Ednrb(s) mice (Mayer Ednrb(s)/Ednrb(s) and C3HeB/FeJ Ednrb(s)/Ednrb(s)) to analyze the effects of modifier loci on the patterning of hypopigmentation. We have confirmed that an Ednrb(s) modifier locus is present on mouse Chromosome 10. This locus is now termed k10, using the nomenclature established by Dunn in 1920. The k10(Mayer) allele is a recessive modifier that accounts for almost all of the genetic variance of dorsal hypopigmentation. Using intercross analyses we identified a second allele of this locus or a closely linked gene termed k10(C3H). The k10(C3H) allele is semidominant and is associated with the penetrance and expressivity of a white forelock phenotype similar to that seen in Waardenburg syndrome. Molecular linkage analysis was used to determine that the k10 critical interval was flanked by D10Mit10 and D10Mit162/D10Mit122 and cosegregates with mast cell growth factor (Mgf). Complementation crosses with a Mgf(Sl) allele (a 3-5-cM deletion) confirm the semidominant white forelock feature of the k10(C3H) allele and the dorsal spotting feature of K10(Mayer) allele. MgF was assessed as a candidate gene for k10(Mayer) and k10(C3H) by sequence and genomic analyses. No molecular differences were observed between the Mayer and C57BL/6J alleles of MgF; however, extensive genomic differences were observed between the C3HeB/FeJ and C57BL/6J alleles. This suggests that alteration of MgF expression in C3H mice may account for the k10(C3H) action on white forelock hypopigmentation. Crosses of Ednrb(s) with Kit(WJ-2) (the receptor for MGF)-deficient mice confirmed the hypothesis that synergistic interaction between the Endothelin and MGF signaling pathways regulates proper neural crest-derived melanocyte development in vivo.

Quantitative trait loci that modify the severity of spotting in piebald mice.

Mice homozygous for the recessive mutation piebald (s) exhibit a white-spotted coat caused by the defective development of neural crest-derived melanocytes. The severity of white spotting varies greatly, depending on the genetic background on which s is expressed. A backcross between two inbred strains of s/s mice that exhibit large differences in the degree of spotting was used to identify six genetic modifiers of piebald spotting on chromosomes 2, 5, 7, 8, 10, and 13. The loci differed in their spatial contribution to spotting on the dorsal versus ventral surfaces of mice; nonadditive interactions were observed between loci on chromosomes 2 and 5. This study underscores the power of using genetic analyses to identify and analyze loci involved in modifying the severity of phenotypic traits in mice.

Superior dislocation of the patella with interlocking osteophytes.

Superior dislocation of the patella with interlocking osteophytes was only once found roentgenologically documented. Such a dislocation occurs without tendon rupture, and can occur with a hyperextension force. Reduction is easily accomplished by manipulation of the patella without anesthesia. Full active motion is present post-reduction. This entity should not be confused with vertical dislocations of the patella.

Rectus femoris muscle: an obstacle in reduction of acute traumatic anterior dislocation of hip in an adult.

A case of traumatic anterior dislocation of the hip that could not be reduced closed is described. On exploring the hip, the rectus femoris muscle was found to be buttonholed by the head of the femur, resulting in failure of closed reduction. Release of the muscle from its origin resulted in easy reduction.

The early complications of subtalar dislocation.

Although the treatments and results of subtalar dislocations are usually considered as nonproblematical, review of 10 cases seen over a 6-year period proved otherwise. Difficulties were encountered with four of these cases consisting of associated foot injuries, failure to recognize the dislocation, incarceration of the dislocation, vascular complications, and iatrogenic infection. The management of these cases is discussed.